Childhood, adolescent, and young adult (CAYA) cancer survivors treated with platinum-based drugs, head or brain radiotherapy, or both have an increased risk of ototoxicity (hearing loss, tinnitus, or ...both). To ensure optimal care and reduce consequent problems—such as speech and language, social–emotional development, and learning difficulties—for these CAYA cancer survivors, clinical practice guidelines for monitoring ototoxicity are essential. The implementation of surveillance across clinical settings is hindered by differences in definitions of hearing loss, recommendations for surveillance modalities, and remediation. To address these deficiencies, the International Guideline Harmonization Group organised an international multidisciplinary panel, including 32 experts from ten countries, to evaluate the quality of evidence for ototoxicity following platinum-based chemotherapy and head or brain radiotherapy, and formulate and harmonise ototoxicity surveillance recommendations for CAYA cancer survivors.
Platinum-based agents, such as cisplatin, form the mainstay of currently used chemotherapeutic regimens for several malignancies; however, the main limitations are chemoresistance and ototoxic side ...effects. In this study we used two different polyphenols, curcumin and ferulic acid as adjuvant chemotherapeutics evaluating (1) in vivo their antioxidant effects in protecting against cisplatin ototoxicity and (2) in vitro the transcription factors involved in tumor progression and cisplatin resistance. We reported that both polyphenols show antioxidant and oto-protective activity in the cochlea by up-regulating Nrf-2/HO-1 pathway and downregulating p53 phosphorylation. However, only curcumin is able to influence inflammatory pathways counteracting NF-κB activation. In human cancer cells, curcumin converts the anti-oxidant effect into a pro-oxidant and anti-inflammatory one. Curcumin exerts permissive and chemosensitive properties by targeting the cisplatin chemoresistant factors Nrf-2, NF-κB and STAT-3 phosphorylation. Ferulic acid shows a biphasic response: it is pro-oxidant at lower concentrations and anti-oxidant at higher concentrations promoting chemoresistance. Thus, polyphenols, mainly curcumin, targeting ROS-modulated pathways may be a promising tool for cancer therapy. Thanks to their biphasic activity of antioxidant in normal cells undergoing stressful conditions and pro-oxidant in cancer cells, these polyphenols probably engage an interplay among the key factors Nrf-2, NF-κB, STAT-3 and p53.
Objective: Effective management of patients diagnosed with ototoxicity is needed to reduce hearing and balance damage which affects communication and life quality. Despite widespread recommendations ...to monitor and manage ototoxicity in an early and effective manner, there is limited evidence to support the actual implementation of these recommendations for affected patient groups in healthcare services across the UK with limited publications available. In this study, an online questionnaire analysed the current practice of ototoxicity management and patient pathways across the UK once the diagnosis of ototoxicity was confirmed, targeting Audiologists, ENTs/AVPs and GPs. Design: Qualitative Survey Study. Study sample: A randomised sample of hearing services in the UK, including audiology departments; GP practices and local health settings were targeted with a total of 134 completed surveys. Results: About 72% reported the absence of ototoxicity management protocols within their centre. Results depicted great inconsistency and variation across the UK in ototoxicity management services provided, treatment modification, monitoring and referral pathways. Conclusion: Developing and advocating national guidelines are intended not only to inform clinical decision making but to provide minimum standards of care in ototoxicity management and offer greater awareness and education to improve patients' quality of life.
Objectives
Ototoxicity is a common disabling side effect of platinum‐based chemotherapy. This study aimed to assess the evidence on the management of platinum‐induced ototoxicity in adult cancer ...patients.
Methods
Four databases were searched up to 1 November 2022. Original studies were included if they reported on a pharmacologic or non‐pharmacologic intervention to prevent or treat platinum ototoxicity in adults. The articles' quality was assessed via two grading scales.
Results
Nineteen randomised controlled trials and five quasi‐experimental studies with 1673 patients were analysed. Eleven interventions were identified, nine pharmacological and two non‐pharmacological. Six of the interventions (sodium thiosulphate, corticoids, sertraline, statins, multivitamins and D‐methionine) showed mild benefits in preventing cisplatin‐induced ototoxicity. Only one trial assessed corticoids as a potential treatment. Overall, only six trials were deemed with a low risk of bias. The majority of studies inadequately documented intervention‐related adverse effects, thereby limiting safety conclusions.
Conclusions
Current interventions have mild benefits in preventing cisplatin‐induced ototoxicity in adult cancer patients. Sodium thiosulphate is the most promising intervention as a preventive strategy. Rigorous, high‐quality research is warranted, encompassing an evaluation of all potential symptoms and innovative treatment modalities.
Cisplatin is one of the most widely used chemotherapeutic drugs for the treatment of cancer. Unfortunately, one of its major side effects is permanent hearing loss. Here, we show that glutathione ...transferase α4 (GSTA4), a member of the Phase II detoxifying enzyme superfamily, mediates reduction of cisplatin ototoxicity by removing 4-hydroxynonenal (4-HNE) in the inner ears of female mice. Under cisplatin treatment, loss of Gsta4 results in more profound hearing loss in female mice compared to male mice. Cisplatin stimulates GSTA4 activity in the inner ear of female wild-type, but not male wild-type mice. In female Gsta4
mice, cisplatin treatment results in increased levels of 4-HNE in cochlear neurons compared to male Gsta4
mice. In CBA/CaJ mice, ovariectomy decreases mRNA expression of Gsta4, and the levels of GSTA4 protein in the inner ears. Thus, our findings suggest that GSTA4-dependent detoxification may play a role in estrogen-mediated neuroprotection.
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•NAD+ level was decreased in cisplatin treated cochlear organ of mice.•NAD+ modulators activated SIRT1, reduced hair cells loss and protected mice hearing.•TES-1025 with cisplatin ...increased mitochondrial contents in hair cells.•The protection of TES-1025 was blocked by SIRT1 inhibitor.
Cisplatin, the most widely used platinum-based anticancer drug, often causes progressive and irreversible sensorineural hearing loss in cancer patients. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. Nicotinamide adenine dinucleotide (NAD+), a co-substrate for the sirtuin family and PARPs, has emerged as a potent therapeutic molecular target in various diseases. In our investigates, we observed that NAD+ level was changed in the cochlear explants of mice treated with cisplatin. Supplementation of a specific inhibitor (TES-1025) of α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), a rate-limiting enzyme of NAD+de novo synthesis pathway, promoted SIRT1 activity, increased mtDNA contents and enhanced AMPK expression, thus significantly reducing hair cells loss and deformation. The protection was blocked by EX527, a specific SIRT1 inhibitor. Meanwhile, the use of NMN, a precursor of NAD+ salvage synthesis pathway, had shown beneficial effect on hair cell under cisplatin administration, effectively suppressing PARP1. In vivo experiments confirmed the hair cell protection of NAD+ modulators in cisplatin treated mice and zebrafish. In conclusion, we demonstrated that modulation of NAD+ biosynthesis via the de novo synthesis pathway and the salvage synthesis pathway could both prevent ototoxicity of cisplatin. These results suggested that direct modulation of cellular NAD+ levels could be a promising therapeutic approach for protection of hearing from cisplatin-induced ototoxicity.
Although chemotherapy and radiotherapy are effective in cancer treatment, different adverse effects induced by these therapeutic modalities (such as ototoxicity) restrict their clinical use. ...Co-treatment of melatonin may alleviate the chemotherapy/radiotherapy-induced ototoxicity.
In the present study, the otoprotective potentials of melatonin against the ototoxicity induced by chemotherapy and radiotherapy were reviewed.
According to the PRISMA guideline, a systematic search was carried out to identify all relevant studies on "the role of melatonin against ototoxic damage associated with chemotherapy and radiotherapy" in the different electronic databases up to September 2022. Sixty-seven articles were screened based on a predefined set of inclusion and exclusion criteria. Seven eligible studies were finally included in this review.
The in vitro findings showed that cisplatin chemotherapy significantly decreased the auditory cell viability compared to the control group; in contrast, the melatonin co-administration increased the cell viability of cisplatin-treated cells. The results obtained from the distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) tests demonstrated a decreased amplitude of DPOAE and increased values of ABR I-IV interval and ABR threshold in mice/rats receiving radiotherapy and cisplatin; nevertheless, melatonin co-treatment indicated an opposite pattern on these evaluated parameters. It was also found that cisplatin and radiotherapy could significantly induce the histological and biochemical changes in the auditory cells/tissue. However, melatonin co-treatment resulted in alleviating the cisplatin/radiotherapy-induced biochemical and histological changes.
According to the findings, it was shown that melatonin co-treatment alleviates the ototoxic damage induced by chemotherapy and radiotherapy. Mechanically, melatonin may exert its otoprotective effects via its anti-oxidant, anti-apoptotic, and anti-inflammatory activities and other mechanisms.
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•Acrolein is known to cause oxidative stress and inflammatory nerve tissue damage.•Lutein is a tetraterpenoid molecule with antioxidant and anti-inflammatory properties.•Lutein ...protects vestibulocochlear nerve tissue from acrolein-associated oxidative and proinflammatory damage.•Lutein may be useful in the prevention or treatment of acrolein-related ototoxicity.
Acrolein is a reactive aldehyde that forms during burning of wood and other fuels. It is also a product of lipid peroxidation (LPO) reactions and is present in cigarette smoke. Acrolein is known to cause oxidative stress and inflammatory nerve tissue damage. Lutein is a tetraterpenoid molecule with antioxidant and anti-inflammatory properties. There appear to be no studies on the effect of lutein on vestibulocochlear nerve damage induced by acrolein. The aim of this study was to investigate the effect of lutein on vestibulocochlear nerve damage induced by acrolein in rats using biochemical and histopathological methods.
The rats were divided into three groups (n = 6, for each group) a healthy control group (HG), an acrolein (ACR) group and a lutein and acrolein (LACR) group. In the LACR group, lutein was administered (1 mg/kg) via oral gavage. The ACR and HG groups received saline via oral gavage. Then, 1 h after the administration of lutein and saline, the LACR and ACR groups were treated with 3 mg/kg of acrolein via oral gavage. This procedure was repeated once a day for 30 days.
The results of biochemical experiments showed that in the vestibulocochlear nerve tissues of the animals treated with acrolein, the levels of malondialdehyde, total oxidants, nuclear factor kappa b, tumor necrosis factor alpha and interleukin 1 beta significantly increased, whereas the levels of total glutathione and total antioxidants decreased as compared to those in the HG and LACR groups. In addition, severe histopathological damage was observed in vestibulocochlear nerve tissue of the acrolein group, whereas this damage was alleviated in the lutein group.
Lutein protected vestibulocochlear nerve tissue from acrolein-associated oxidative and proinflammatory damage. This suggests that lutein might be useful in preventing or treating acrolein-induced ototoxicity.
Gentamicin has been widely prescribed since the last two decades despite its ototoxicity and nephrotoxicity. Bisdemethoxycurcumin (BDMC) is an affordable and safe curcuminoid with medicinal ...properties. We aimed to understand the effects of BDMC on the gentamicin-induced hair cell damage in mouse cochlear UB/OC-2 cells, in order to elucidate the therapeutic potential of BDMC against gentamicin-induced ototoxicity.
We quantified the cell membrane potential and examined the regulators and cascade proteins in the intrinsic pathway of hair cell apoptosis. Mouse cochlear UB/OC-2 cells were treated with BDMC before exposure to gentamicin. The effects of BDMC on hair cell viability, mitochondrial function, and apoptosis-related proteins were examined by flow cytometry, western blot, and fluorescent staining.
Our results revealed that BDMC reversed gentamicin-mediated cycle arrest at the G
/M phase, stabilizing the mitochondrial membrane potential, decreasing cleaved caspase proteins, and successfully reversing hair cell apoptosis.
BDMC is a potential agent for reducing gentamicin-induced ototoxicity.
The chemotherapeutic agent cisplatin is renowned for its ototoxic effects. While hair cells in the cochlea are established targets of cisplatin, less is known regarding the afferent synapse, which is ...an essential component in the faithful temporal transmission of sound. The glutamate aspartate transporter (GLAST) shields the auditory synapse from excessive glutamate release, and its loss of function increases the vulnerability to noise, salicylate, and aminoglycosides. Until now, the involvement of GLAST in cisplatin‐mediated ototoxicity remains unknown. Here, we test in mice lacking GLAST the effects of a low‐dose cisplatin known not to cause any detectable change in hearing thresholds. When administered at nighttime, a mild hearing loss in GLAST KO mice was found but not at daytime, revealing a potential circadian regulation of the vulnerability to cisplatin‐mediated ototoxicity. We show that the auditory synapse of GLAST KO mice is more vulnerable to cisplatin administration during the active phase (nighttime) when compared to WT mice and treatment during the inactive phase (daytime). This effect was not related to the abundance of platinum compounds in the cochlea, rather cisplatin had a dose‐dependent impact on cochlear clock rhythms only after treatment at nighttime suggesting that cisplatin can modulate the molecular clock. Our findings suggest that the current protocols of cisplatin administration in humans during daytime may cause a yet undetectable damage to the auditory synapse, more so in already damaged ears, and severely impact auditory sensitivity in cancer survivors.
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